This application addresses the broad Challenge Area (15) Translational Science, and Specific Challenging Topic 15-NS-103 as our proposal is a "Demonstration of "proof-of-concept" for a new therapeutic approach in a neurological disease. The application may also apply to the Broad Challenge Area (03) Biomarkers discovery and validation, and Specific Challenging Topics: 03-NS-102 Standardization and validation of neurological biomarkers, as we are examining levels of BDNF and synaptic plasticity markers that can be implemented as biomarkers for traumatic brain injury 03-DK-105 Nutrient biomarkers, as our proposal is related to the identification and validation of sensitive and predictive biomarkers to evaluate status of a specific nutrient (curcumin derivative). Traumatic brain injury (TBI) affects more than 1,500,000 Americans every year, making TBI one of the most common causes of disability for the general population. The treatment of TBI is exceptionally complex as TBI can result from a large variety of insults and mechanisms to broad brain areas that compromise neural function with long-term cognitive implications. Therefore, proper treatment of TBI should require therapies that can properly address the multiple weaknesses, particularly those related to long-term neuronal function and plasticity underlying the cognitive and behavioral impairment. To address the need for broadly neuroprotective drugs, we have identified a potent synthetic derivative of curcumin, namely CNB-001, that may comprehensively normalize several of the neuronal processes that are disrupted after TBI. The natural product curcumin, which is the precursor of CNB-001, has shown excellent efficacy in counteracting dysfunction in several models of neurodegenerative diseases such as Alzheimer's, cerebral ischemia, promoting neurogenesis in the adult hippocampus, and in our hands, counteracting learning impairment resulting after TBI. CNB-001 has the advantage to be several times more potent than curcumin, orally active with rapid absorption into the blood and to the brain. CNB-001 has both neuroprotective and neuronal function enhancing properties, suggesting CNB-001 as a unique candidate drug for treating TBI and other neurodegenerative disorders. To assay the efficacy of our compound CNB-001, we will use the fluid percussion injury model (FPI) for TBI that produces a closed head wound characterized by marked physiological changes with a relative paucity of histological damage under moderate injury. The goal of this project is to explore the therapeutic potential of CNB-001 for TBI and to determine potential mechanisms for these actions. Specifically, we will evaluate the ability of CNB-001 supplemented in the diet to restore synaptic plasticity and energy metabolism disrupted after TBI, in conjunction with CNB-001 effects on counteracting cognitive, mood disorders, and motor dysfunction. It is noteworthy that our comprehensive study of CNB-001 efficacy considers the analysis of motor behavior beyond the brain. Our preliminary data are very exciting to demonstrate that CNB-001 counteracts a reduction in BDNF levels in the spinal cord after TBI. These data are very exciting and relevant to help understanding gait dysfunction common in TBI patients, and offering the possibility for developing a therapy. In addition, given preliminary evidence showing the potential of CNB-001 to affect BDNF activity, and the capacity of BDNF to modulate synaptic plasticity and energy metabolism, we will evaluate the role of BDNF mediating some of the actions of CNB-001. We will study molecular mechanisms in conjunction with their relationship to behavior, expecting to provide evidence for applying CNB-001 as a therapeutic for treating TBI patients. Based on all above consideration, our specific challenges are: 1) to develop a clinically effective drug for treating TBI with the capacity to protect neurons to damage in response to multiple stresses, and to support synaptic function and energy supply to cells;2) to deliver the drug to the brain in a minimally invasive fashion for optimal applicability even before the insult/challenge. PUBLIC HEALTH RELEVANCE: The goal of this project is to explore the therapeutic potential of a broad-spectrum drug for TBI and to determine its potential mechanisms using fluid percussion injury model in rats. We have a comprehensive approach to evaluate the ability of CNB-001 to restore synaptic plasticity and energy metabolism in conjunction with counteracting dysfunction in cognition, mood, and locomotion, in the brain and spinal cord. We expect to generate valuable pre-clinical information that will entitle us to initiate the steps for seeking IND approval.